Estimates of SARS-CoV-2 Seroprevalence and Incidence of Primary SARS-CoV-2 Infections Among Blood Donors, by COVID-19 Vaccination Status — United States, April 2021–September 2022

Changes in testing behaviors and reporting requirements have hampered the ability to estimate the U.S. SARS-CoV-2 incidence (1). Hybrid immunity (immunity derived from both previous infection and vaccination) has been reported to provide better protection than that from infection or vaccination alone (2). To estimate the incidence of infection and the prevalence of infection- or vaccination-induced antibodies (or both), data from a nationwide, longitudinal cohort of blood donors were analyzed. During the second quarter of 2021 (April-June), an estimated 68.4% of persons aged ≥16 years had infection- or vaccination-induced SARS-CoV-2 antibodies, including 47.5% from vaccination alone, 12.0% from infection alone, and 8.9% from both. By the third quarter of 2022 (July-September), 96.4% had SARS-CoV-2 antibodies from previous infection or vaccination, including 22.6% from infection alone and 26.1% from vaccination alone; 47.7% had hybrid immunity. Prevalence of hybrid immunity was lowest among persons aged ≥65 years (36.9%), the group with the highest risk for severe disease if infected, and was highest among those aged 16-29 years (59.6%). Low prevalence of infection-induced and hybrid immunity among older adults reflects the success of public health infection prevention efforts while also highlighting the importance of older adults staying up to date with recommended COVID-19 vaccination, including at least 1 bivalent dose.*,†.

* https://www.cdc.gov/coronavirus/2019-ncov/your-health/risks-getting-verysick.html † https://www.cdc.gov/coronavirus/2019-ncov/vaccines/index.html § Blood donors who donated at least twice during the year before July 2021 were included in the cohort, because they might represent persons who were more likely to donate frequently. Among donors who donated more than once during a quarter, one sample was selected at random for testing.
April-June 2021 were tested for antibodies against the spike (S) and nucleocapsid (N) proteins. Beginning in 2022, up to one blood donation sample per donor was randomly selected each quarter and tested using the Ortho VITROS SARS-CoV-2 Quantitative S immunoglobulin G ¶ and total N antibody** tests. Both SARS-CoV-2 infection and COVID-19 vaccination result in production of anti-S antibodies, whereas anti-N antibodies only result from infection. At each donation, blood donors were asked if they had received a COVID-19 vaccine. Using vaccination history and results of antibody testing, the prevalence of the U.S. population aged ≥16 years with vaccineinduced, infection-induced, or hybrid immunity was estimated for four 3-month periods (April-June 2021, January-March 2022, April-June 2022, and July-September 2022); in addition, the proportion of persons who transitioned from one immune status to another by quarter was estimated. Analysis was limited to 72,748 (51.0%) donors for whom it was possible to ascertain immune status during each period using their prior classification (e.g., previously infected or vaccinated), antibody testing results, and their vaccination status at the time of each donation. † † The sample data were weighted to account for selection into the study cohort, for nonresponse during the four analysis periods, and for demographic differences between the blood donor population and the overall U.S. population. The weights were obtained through a combination of stratification and raking, an iterative weighting adjustment procedure (4). Rates of infection among those previously uninfected were estimated for each period by determining the percentage of anti-N-negative persons seroconverting to anti-N-positive from one 3-month period included in the study to the next.    Among persons with no previous infection, the incidence of first infections during the study period (i.e., conversion from anti-N-negative to anti-N-positive) was higher among unvaccinated persons (Table). From April-June 2021 through January-March 2022, the incidence of first SARS-CoV-2 infections among unvaccinated persons was 67.0%, compared with 26.3% among vaccinated persons (p<0.05). From January-March 2022 through April-June 2022, the incidence among unvaccinated persons was 21.7% and was 13.3% among vaccinated persons. Between April-June 2022 and July-September 2022, the incidence among unvaccinated persons was 28.3%, compared with 22.9% among vaccinated persons (p<0.05). Incidence of first SARS-CoV-2 infections was higher among younger than among older persons and was lower among Asian persons than among other racial and ethnic populations, but the differences among groups narrowed over time.

Discussion
Both infection-induced and hybrid immunity increased during the study period. By the third quarter of 2022, approximately two thirds of persons aged ≥16 years had been infected with SARS-CoV-2 and one half of all persons had hybrid immunity. Compared with vaccine effectiveness against any infection and against severe disease or hospitalization, the effectiveness of hybrid immunity against these outcomes has been shown to be higher and wane more slowly (2). This

FIGURE 2. Prevalences of vaccine-induced, infection-induced, and hybrid* immunity † against SARS-CoV-2 among blood donors aged ≥16 years, by age group -United States, April 2021-September 2022
Options de = 7.5" ats = 5.0" s = 4.65" n = 3.57" increase in seroprevalence, including hybrid immunity, is likely contributing to lower rates of severe disease and death from COVID-19 in 2022-2023 than during the early pandemic. † † † The prevalence of hybrid immunity is lowest in adults aged ≥65 years, likely due to higher vaccination coverage and earlier availability of COVID-19 vaccines for this age group, as well as to higher prevalences of behavioral practices to avoid infection (5). However, lower prevalences of infection-induced and hybrid immunity could further increase the risk for severe disease in this group, highlighting the importance for adults aged ≥65 years to stay up to date with COVID-19 vaccination and have easy access to antiviral medications. COVID-19 vaccine efficacy studies have reported reduced effectiveness against SARS-CoV-2 infection during the Omicron-predominant period compared with earlier periods and have shown that protection against infection wanes more rapidly than does protection against severe disease (6,7). In this study, unvaccinated persons had higher rates of infection (as evidenced by N antibody seroconversion) than did vaccinated persons, indicating that vaccination provides some protection against infection. The differences in incidence could also be due to systematic differences between vaccinated and unvaccinated persons in terms of the prevalence of practicing prevention behaviors such as masking and physical distancing. The relative † † † https://covid.cdc.gov/covid-data-tracker/#datatracker-home (Accessed May 25, 2023). difference in infection rates narrowed during the most recent months, possibly because of waning of vaccine-induced protection against infection in the setting of increased time after vaccination or immune evasion by the SARS-CoV-2 Omicron variant. The narrowing of difference in infection rates might also be attributable to increasing similarities in behavior among vaccinated and unvaccinated persons during late 2022 (8).
The findings in this report are subject to at least six limitations. First, although COVID-19 booster vaccine doses and reinfections can strengthen immunity (9,10), this analysis did not account for these effects because blood donor vaccination history did not include the number of doses received, and data on reinfections were not captured. Second, immunity wanes over time, but time since vaccination or infection was not included in the analysis (2). Third, vaccination status was self-reported, potentially leading to misclassification. Fourth, although the results were adjusted based on differences in blood donor and general population demographics, estimates from blood donors might not be representative of the general population; thus, these results might not be generalizable. Fifth, vaccinated and unvaccinated persons might differ in other ways not captured by this analysis (8), nor can causality be inferred from the results on relative infection incidence. Finally, if both vaccination and infection occurred between blood donations included in the study, the order of occurrence could not be determined, and some unvaccinated donors might have been

Summary
What is already known about this topic? SARS-CoV-2 hybrid immunity (immunity derived from both previous infection and vaccination) has been reported to provide better protection than that from infection or vaccination alone.
What is added by this report?
By the third quarter of 2022, an estimated 96.4% of persons aged ≥16 years in a longitudinal blood donor cohort had SARS-CoV-2 antibodies from previous infection or vaccination, including 22.6% from infection alone and 26.1% from vaccination alone; 47.7% had hybrid immunity. Hybrid immunity prevalence was lowest among adults aged ≥65 years.
What are the implications for public health practice?
Low prevalence of infection-induced and hybrid immunity among older adults, who are at increased risk for severe disease if infected, reflects the success of public health infection prevention efforts while also highlighting the importance of this group staying up to date with recommended COVID-19 vaccination, including at least 1 bivalent dose.
vaccinated before infection and thus misclassified; in 2022, this was uncommon and occurred in <0.5% of donors during any 3-month period.
This report found that the incidence of first-time SARS-CoV-2 infection was lower among persons who had received COVID-19 vaccine than among unvaccinated persons and that infection-induced and hybrid immunity have increased but remain lowest in adults aged ≥65 years. These adults have consistently had a higher risk for severe disease compared with younger age groups, underscoring the importance of older adults staying up to date with recommended COVID-19 vaccination, including at least 1 bivalent dose.